Abstract
Background:
Resistin, a novel adipokine, is elevated in patients with type 2 diabetes and may play a role in the vascular complications of this disorder. One recent study has shown that resistin has a proinflammatory effect on endothelial cells. However, there is no information on whether resistin could also affect vascular smooth muscle cells (SMCs). Thus, the purpose of this study was to assess whether resistin could induce SMC proliferation and to study the mechanisms whereby resistin signals in SMCs.
Methods and results:
Human aortic smooth muscle cells (HASMCs) were stimulated with increasing concentrations of resistin for 48 hours. Cell proliferation was induced by resistin in a dose-dependent manner as assessed by direct cell counting. To gain more insights into the mechanism of action of resistin, we investigated the extracellular signal-regulated kinase (ERK) and/or phosphatidylinositol 3-kinase (PI3K) signaling pathways. Transient phosphorylation of the p42/44 mitogen-activated protein kinase (ERK 1/2) occurred after addition of resistin to HASMCs. U0126, a specific inhibitor of ERK phosphorylation, significantly inhibited ERK 1/2 phosphorylation and reduced resistin-simulated proliferation of HASMCs. LY294002, a specific PI3K inhibitor, also significantly inhibited HASMC proliferation after resistin stimulation.
Conclusions:
Our results demonstrate that resistin induces HASMC proliferation through both ERK 1/2 and Akt signaling pathways. The proliferative action exerted by resistin on HASMCs may account in part for the increased incidence of restenosis in diabetes patients.
MeSH terms
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Aorta / cytology
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Arteriosclerosis / metabolism
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Butadienes / pharmacology
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Cell Division / drug effects
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Cells, Cultured / cytology
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Cells, Cultured / drug effects
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Cells, Cultured / enzymology
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Chromones / pharmacology
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Diabetes Complications / metabolism
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Hormones, Ectopic / antagonists & inhibitors
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Hormones, Ectopic / pharmacology*
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Imidazoles / pharmacology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / physiology*
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / physiology*
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Morpholines / pharmacology
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects*
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Muscle, Smooth, Vascular / enzymology
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / drug effects*
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Myocytes, Smooth Muscle / enzymology
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Nitriles / pharmacology
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Pyridines / pharmacology
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Recombinant Proteins / pharmacology
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Resistin
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Signal Transduction / drug effects*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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Butadienes
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Chromones
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Hormones, Ectopic
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Imidazoles
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Morpholines
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Nitriles
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyridines
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Recombinant Proteins
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Resistin
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U 0126
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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SB 203580